Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder

Marisa W. Friederich, Sharita Timal, Christopher A. Powell, Cristina Dallabona, Alina Kurolap, Sara Palacios-Zambrano, Drago Bratkovic, Terry G.J. Derks, David Bick, Katelijne Bouman, Kathryn C. Chatfield, Nadine Damouny-Naoum, Megan K. Dishop, Tzipora C. Falik-Zaccai, Fuad Fares, Ayalla Fedida, Ileana Ferrero, Renata C. Gallagher, Rafael Garesse, Micol GilbertiCristina González, Katherine Gowan, Clair Habib, Rebecca K. Halligan, Limor Kalfon, Kaz Knight, Dirk Lefeber, Laura Mamblona, Hanna Mandel, Adi Mory, John Ottoson, Tamar Paperna, Ger J.M. Pruijn, Pedro F. Rebelo-Guiomar, Ann Saada, Bruno Sainz, Hayley Salvemini, Mirthe H. Schoots, Jan A. Smeitink, Maciej J. Szukszto, Hendrik J. ter Horst, Frans van den Brandt, Francjan J. van Spronsen, Joris A. Veltman, Eric Wartchow, Liesbeth T. Wintjes, Yaniv Zohar, Miguel A. Fernández-Moreno, Hagit N. Baris, Claudia Donnini, Michal Minczuk, Richard J. Rodenburg, Johan L.K. Van Hove

Research output: Contribution to journalArticlepeer-review


Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNAGln). mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNAGln and mitochondrial protein translation are deficient in patients’ fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex.

Original languageEnglish
Article number4065
JournalNature Communications
Issue number1
StatePublished - 1 Dec 2018

Bibliographical note

Funding Information:
We would like to thank the families for their participation in this study. We thank the mitochondrial diagnostics group (muscle lab, cell culture lab, and DNA lab) of the Radboud Center for Mitochondrial Medicine (RCMM) at the Translational Metabolic Laboratory, Radboud UMC, as well as Carla Onnekink, Jeff Willemsen, Daisy Dalloyaux, and Sander van de Groenendaal for excellent technical assistance. Mareike Muhlmeister and Ulrich Brandt are thanked for performing mass spectrometry experiments. We would like to acknowledge the Genome Technology Center at the Radboud UMC and BGI Copenhagen for providing the exome sequencing service for patients P1A and P1B. We like to thank the staff of the Colorado Fetal Care Center, the Children’s Hospital Colorado fetal cardiology and neonatology programs and C. Freehauf, RN, CGC for the expert clinical care of family 3. C.A.P., M.J.S., P.R.-G. and M.M. were supported by the core funding from the Medical Research Council, UK (MC_U105697135 and MC_UU_00015/4). J.V.H. and M.W.F. were supported by Miracles for Mito, the Children’s Hospital Colorado Foundation and University of Colorado Foundation. This work was supported by Telethon Foundation, Italy grant GGP15041 to C.D. This work was also supported by Instituto de Salud Carlos III, http://, PI13/00556 to R.G.; FEDER funds from the E.U. to R.G. and Instituto de Salud Carlos III,, PI16/00789 to R.G. and M.A.F-M. P.R.-G. was supported by Fundação para a Ciência e a Tecnologia (PD/BD/105750/2014).

Publisher Copyright:
© 2018, © 2018, The Author(s).

ASJC Scopus subject areas

  • Chemistry (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Physics and Astronomy (all)


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